In the prior funding period, we demonstrated that conditional elimination of the Glycogen Synthase Kinase-3s (GSK-3s), a and , in the embryonic nervous system results in remarkable dysregulation of neural progenitor homeostasis. This result has important translational significance because of the widespread use of a GSK-3 inhibitor, lithium, in clinical practice. We hypothesize that inactivation of GSK-3s renders progenitors incapable of responding to the extracellular signals that normally regulate conversion of radial progenitors to neurons and intermediate neuronal precursors (INPs). We now propose definitive mouse genetic experiments to assess mechanisms of this GSK-3 regulation (Aims I and II). Further, we will use a chemical genetics approach to determine if reinduction of GSK-3 activity in GSK-3 deficient progenitors will result in enhanced neurogenesis (Aim III). Finally we will ask whether GSK-3 signaling regulates neural progenitors in the adult dentate gyrus (Aim IV). This work will reveal the functional potential and mechanisms of GSK-3 regulation of neural progenitors in mammals. The work will also provide information on previously unrecognized potential effects of lithium a drug commonly used in clinical practice, increasingly in children. Finally our results may suggest new ways to expand neural progenitor populations in the setting of neural transplantation. PUBLIC HEALTH RELEVANCE: We propose that a specific protein, GSK-3, is a master regulator of neural stem cells. This function of GSK-3 requires investigation because a GSK-3 inhibitor, lithium, is commonly used in clinical practice, increasingly in children. Our results may also suggest new ways to expand neural stem cells in the setting of neural transplantation